tbuckley/cabot-search huggingface dataset:
Development of an artificial intelligence algorithm for adjuvant chemotherapy based on a nationwide registry of patients with gastric cancer by the Japanese Gastric Cancer Association (JGCA).
Authors: Yasuhide Yamada, Ami Kamada, Yoshinori Kabeya, Sumito Yoshida, Hitoshi Harada, Naoki Urakawa, Shingo Kanaji, Yuma Nakamura, Kengo Nagashima, Hiroya Takeuchi, Yuichiro Doki, Yuko Kitagawa, Yasuhiro Kodera, Yoshihiro Kakeji
Journal: Journal of Clinical Oncology (2023)

4063 Background: Recent marked advances in machine learning have led to expectations of the clinical application of artificial intelligence (AI) to support medical care. Methods: A survival analysis model which consisted of 31 covariates was adopted for AI algorithms using machine learning and these were constructed using clinical data sets for training. The performance of AI algorithms was evaluated in order to determine the optimal chemotherapy including surgery alone without any adjuvant chemotherapy with the highest survival rate for each patient. This involved using clinical data for verification to compare survival of an AI-recommended treatment group, for which therapy recommended by AI was actually administered, with an AI-deprecated group, for which therapy recommended by AI was not administered. Results: The clinical characteristics of 23653 patients and treatment are described in the Table from 2011 to 2018 in a nationwide registry of gastric cancer patients in Japan by the Japanese Gastric Cancer Association and were made available for this study. S-1 monotherapy was used the most frequently of all adjuvant chemotherapy in this study. We used the "restricted mean overall survival time" (RMST) of all the patients as metrics. The RMST in the AI-recommended and the AI-deprecated groups were 51.4 and 47.5 months, respectively. Patient data for the verification were matched baseline characteristics by the propensity score. This model predicted effectively overall survival after gastrectomy. The RMST of over 80 years old patients were 43.9 in the AI-recommended and 38.3 months in the AI-deprecated, respectively. This AI algorithm recommended adjuvant S-1 more frequently for patients with higher age, male, American Society of Anesthesiologists – physical status 2, Eastern Cooperative Oncology Group performance status 1, pT3/pT4, pN2/pN3, more than the upper normal limit of preoperative blood urea nitrogen, macroscopic types 2/3, differentiated adenocarcinoma, Roux-en-Y reconstruction, and Clavien-Dindo classification grade II/III. The RMST for pStage IIA/IIB/IIIA/IIIB/IIIC were 55.7/53.9/50.3/45.7/42.2 months in the AI-recommended and 55.1/50.7/43.9/36.9/32.0 months in the deprecated. This AI algorithm showed a higher survival rate in pStage III patients particularly. Conclusions: The AI algorithm could readily be integrated into clinical practice to choose adequate adjuvant chemotherapy for each patient based on each patient's baseline data because it trained and verified the nationwide registry has good predictive performance. [Table: see text]
Efficacy of low dose sorafenib and capecitabine in the management of hepatocellular cancer.
Authors: Abdul Mateen, Famya Abdullah, Muhammad Saeed Akhtar, Arif Moin Quraishi, Amir Sattar, Quratul Ain Hashmi, Isharat Shehrood Sanwal, Faryal Jamil, Rida Safdar, Allah Rakha Adil
Journal: Journal of Clinical Oncology (2023)

e16117 Background: Hepatocellular cancer (HCC) is one of the commonest cancers in Pakistan due to endemic hepatitis B and C diseases. Its incidence is continuously rising due to lack of public awareness and lack of routine screening of the affected population. Most of the patients present in advanced stage of the disease excluding option for curative surgical options. These patients are mostly not fit enough to tolerate systemic therapies in full doses. So, we have to adapt ourselves to lower dosage so that it can be tolerated without many untoward side effects. Methods: This study was aimed to assess the efficacy of low dose sorafenib (400 mg daily in two divided doses) and capecitabine (1000 mg daily in two divided doses) in advanced hepatocellular carcinoma. Patients were prescribed this treatment for six months and then response was assessed using computed tomography or ultrasound and alpha fetoprotein (AFP) levels. Progression-free survival (PFS) and overall survival (OS) were also assessed. Results: Total of one-hundred fifty-five patients were enrolled. One hundred thirteen patients completed the treatment for six months and were evaluated for response. A total of 28 (25%) of patients progressed during treatment and were shifted to other treatment options. Nine patients (8%) had complete response, thirty-four (30%) had partial response, forty-two (37%) had stable disease and twenty-eight (25%) had progressive disease. Seventy-four patients (65%) showed significant reduction in AFP levels. A total of 85/113 (75%) patients were available for assessment of PFS and OS. Two-year PFS and OS were 32% and 43% respectively. Mean and median PFS (year) were 1.82 ±0.19 (95% confidence interval 1.48 to 2.17) and 1.27±0.16 (95% confidence interval 0.94 to 1.57) respectively. Mean and median OS (year) were 2.73 ±0.24 (95% confidence interval 2.39 to 3.16) and 2.27±0.13 (confidence interval 2.02 to 2.54) respectively. Twenty-six patients had one or more episode of grade 2 diarrhea, eleven patients developed encephalopathy, thirteen patients developed hand foot syndrome and nineteen patients showed grade 2 thrombocytopenia. Conclusions: Low dose sorafenib and capecitabine is effective in the treatment of advanced HCC with excellent tolerability and minimal toxicity.
A study of frontline therapy in adults &gt;80 years with chronic lymphocytic leukemia (CLL).
Authors: Mazie Tsang, Paul Joseph Hampel, Kari G. Rabe, Wei Ding, Jose Francisco Leis, Saad Kenderian, Yucai Wang, Eli Muchtar, Amber Koehler, Curtis A Hanson, Min Shi, Susan L. Slager, Neil E. Kay, Sameer Ashok Parikh
Journal: Journal of Clinical Oncology (2023)

12057 Background: AlthoughCLL primarily affects older adults (median age 71 years), limited data exists about the outcomes of adults who are ≥80 years old because they are under-enrolled on clinical trials. Methods: The Mayo Clinic CLL Database was used to conduct a retrospective cohort study of adults ≥80 years at the time of frontline CLL treatment. Kaplan-Meier analysis was used to plot OS, and cumulative incidence was used to plot TTNT, accounting for competing risk of death. The Mayo Clinic IRB approved the study. Results: Our study included 216 patients with CLL who were age ≥80 years at the time of frontline CLL therapy between 1/1995 and 11/2022 (Table). The median time from CLL diagnosis to initiation of frontline therapy was 3.1 years. The median OS after start of frontline therapy was 3.9 years. The median OS was 3.3 years (95% CI 2.6–4.2) for patients who received alkylating agents (e.g., chlorambucil, n=96), 3.8 years (95% CI 2.8–not reached [NR]) for purine analogues (e.g., fludarabine, n=11), 3.9 years (95% CI 3.2–4.9) for anti-CD20 monoclonal antibody monotherapy (e.g., obinutuzumab, n=64), and not reached (95% CI 3.3-NR) for novel agents (n=43) (P=0.02). The types of novel agents included ibrutinib (n=19), acalabrutinib (n=16), venetoclax (n=7), and orelabrutinib (n=1). There was no difference in OS between 36 patients who received a BTKi compared to the 7 patients who received venetoclax-based therapy. At a median follow-up time of 6.7 years from the first visit, 143 patients died from the following: progressive CLL (n=63), infections (n=12), other cancer (n=11), non-CLL reasons (n=21). Cause of death was unavailable for 36 patients. On multivariable analyses, older age (i.e., any 5-year increase in age) was associated with a 50% increased risk of death (HR 1.5, 95% CI 1.2-1.9, p=0.001), and treatment with non-novel agents was associated with 3.2 times increased risk of death (HR 3.2, 95% CI 1.2-8.9, p=0.02). Of the 216 patients, 76 patients required second-line therapy; the median TTNT was 4.2 years (95% CI 2.9-NE). The most used second-line agents were monoclonal antibodies alone (20/76, 26%) and single-agent alkylators (18/76, 24%). Conclusions: When compared to all other CLL treatments, novel agents such as BTKi and venetoclax-based treatments are associated with significantly improved OS in patients with CLL ≥80 years old when used in the frontline setting. [Table: see text]
Health equity challenges facing testing, evaluation, and implementation of multi-cancer early detection tests.
Authors: Michelle M. LeBeau, Larry Kessler, Carmen Guerra, Esther Krofah, Kate Brain
Journal: Journal of Clinical Oncology (2023)

e15051 Background: The development of Multi Cancer Early Detection markers may herald a new approach to screening and detection of multiple cancers simultaneously via various biological assays. At each stage of development and evaluation of these tests, and especially at implementation, challenges to ensuring equitable access to advancements in cancer prevention, screening, diagnosis, and treatment arise. Diverse research study populations and methods are key when investigating the efficacy of screening tools in practice. Health equity encompasses all parts of research study and design, particularly increasing diversity in research study populations and methods to reflect intended populations of study and document how MCEDs may impact demographic groups differently. Methods: The MCED Consortium is a not-for-profit group of volunteers, advisors, and companies from the US and the UK spanning a wide range of expertise in biomarker evaluation and implementation, with a special focus on clinical practice, health equity, and communication ( https://www.mced.info/ ). We are developing recommendations for the evaluation of test utility, appropriate prioritized populations for screening or early detection, downstream actions in health systems, achieving health equity, and addressing the communication challenges related to this new, potentially revolutionary generation of tests. Results: The MCED consortium has made recommendations in the domains of investigator, participant level, and study design features. The Consortium also has identified key questions for MCED researchers and users regarding equitable access, acceptance, and follow-up. An emerging challenge relates to the release of these tests to selected populations via the laboratory-developed test pathway; which will almost certainly disproportionately increase access to insured and higher socioeconomic status populations. Conclusions: In this MCED Consortium presentation, we will discuss the barriers to ensuring adequate clinical trial diversity and evaluation of MCEDs and how to optimize equity during their current and near-term distribution.
A four-tier classification system for studying homologous recombination repair gene reversion mutations as a mechanism of resistance to PARP inhibitors and platinum chemotherapy.
Authors: Qiuxiang Ou, Miao-fang Wu, Yutong Ma, Xiaoying Wu, Yan Shi, Minyi Zhu, Yang Shao, Jing Li
Journal: Journal of Clinical Oncology (2023)

3140 Background: Pathogenic mutations in homologous recombination repair (HRR) genes are highly associated with the oncogenesis of multiple cancers and represent favorable biomarkers for platinum (Pt)-based chemotherapy and poly ADP ribose polymerase inhibitors (PARPi). While the development of drug resistance by restoring protein function via secondary mutation is commonly observed, a thorough analysis of the landscape of HRR gene reversion mutation is lacking. Methods: A real-world database with ~13,000 pan-cancer patients who underwent targeted next-generation sequencing and contained a primary germline or somatic pathogenic mutation of 25 pre-defined HRR genes, including ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, ERCC3, FANCA, FANCC, FANCD2, FANCI, FANCL, MRE11A, NBN, PALB2, RAD51, RAD51C, RAD51B, RAD51D, RAD54L, and WRN, was used to identify HRR secondary mutations, which were further classified into four tiers by mutation type and intended reversion mechanism. Patient’s clinical data and treatment history were retrospectively reviewed. Results: The potential mechanism of HRR gene reversion was categorized into four tiers, including Tier 1 (single nucleotide variation, SNV), Tier 2 (frameshift), Tier 3 (deletion), and Tier 4 of other mutation types that were not further discussed in this study. A total of 42 patients were identified with Tier 1/2/3 secondary HRR gene mutations in the presence of a primary pathogenic germline (N = 32) or somatic (N = 10) mutation. BRCA1 (15/42, 35.7%) and BRCA2 (23/42, 54.8%) were most frequently observed in this cohort with significant enrichment of exon 11 aberrations of both genes. The other HRR genes identified of Tier 1/2/3 reversion mutations included PALB2 (N = 3, Tier 3) and RAD51D (N = 1, Tier 1). More specifically, a majority of BRCA1 reversion mutations (8/15) were Tier 1 SNV, while the most prevalent reversion mechanism for BRCA2 was Tier 3 deletion, which accounted for 60.9% (14/23) of all BRCA2 cases with a median deleted length of 1164 bp (range: 153 – 6745 bp). Furthermore, we reported the treatment history data of three cancer patients (pancreatic, prostate, and lung, respectively) demonstrated the acquisition of BRCA2 reversion mutations (Tier 2 and Tier 3) at post-Pt/Olaparib in the presence of a primary germline BRCA2 pathogenic mutation, strongly suggestive of the role of reversion mutations in driving resistance to Olaparib or Pt-chemotherapy. Conclusions: Owing to a large-scale real-world dataset, we retrospectively investigated the landscape of the reversion mechanism of HRR genes and established a four-tier classification system for secondary HRR mutations in the presence of primary germline/somatic pathogenic HRR mutations. This study is of great clinical value in studying mechanisms of drug resistance to Pt-chemotherapy and PARPi.
Effect of overexpression of ERK1/2 and MDR1 on chemoresistance in advanced gastric cancer patients.
Authors: Sushmita Ghosh, Ranita Pal, Tanuma Mistry, Pranab Kumar Sahoo, Sutapa Mahata, Sinjini Sarkar, Trisha Choudhury, Raya Banerjee, Jayanta Chakrabarti, Kalyan Kusum Mukherjee, Neyaz Alam, Syamsundar Mandal, Vilas Nasare
Journal: Journal of Clinical Oncology (2023)

e16051 Background: Gastric cancer (GC) is late diagnosed disease with a poor prognosis. The emergence of multidrug resistance (MDR) increases the disease burden, and treatment failure in the patients. Several molecular and circulating biomarkers have been identified and evaluated for the clinical relevance in the management of gastric cancer. The aim of this study is to decipher the involvement of ERK1/2 and MDR1 in relation to MDR phenotype and major clinicopathological characteristics in gastric cancer patients. This will help to select effective drug combinations to improve the treatment success rate. Methods: This study recruited 64 individuals with newly diagnosed gastric cancer between 2019 and 2022. Patients were recommended for surgery or neoadjuvant chemotherapy (NACT). NACT group treated with docetaxel (60 mg/m2), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2), and 5-fluorouracil (2,600 mg/m2 as a 24 hr infusion), all given on day 1 and administered every 2 weeks before surgery. Based on CECT report, patients were categorized as responders (CRs), partial responders (PRs), and non-responders (NRs). Tissue and blood samples were analyzed for ERK1/2 and MDR1expression using IHC, immuno-blotting and qRT-PCR analyses. Rhodamine123 (Rh123) accumulation assay and flowcytometry was performed to measure the degree of resistance among patients. Descriptive statistics, and Pearson’s Chi-square test was carried out to evaluate the expression distribution of ERK1/2 and MDR1. Results: Out of 64 patients, between the ages of 41-60 (53.08±10.51), 54.5% have ≥5 cm tumor size in the antrum site (56.1%) and diagnosed with stage III (56.1%). Majority of observations were intestinal type (60.6%) with lymphovascular invasion (71.2%). Among all 29.4%, 20.6% and 50.0% were CRs, PRs, &amp; NRs respectively and 36.5% patients underwent NACT. The IHC scoring analysis revealed 25 (37.9%) &amp; 18 (28.6%) individuals for ERK1/2 and 18 (27.3%) and 26 (39.4%) individuals for MDR1 had moderate to strong expressions respectively. Simultaneously, the expressions were highly significant with tumor site (antrum), tumor size (≥5 cm), wall thickening (radiological finding), signet ring cell carcinoma, grade 3, stage III (T3N2), NRs, lymphovascular, peritoneal and serosal invasions (p=0.000). ERK1/2 was more prevalent in diffuse type patients (p=0.000). Also, protein and mRNA level for both genes were more pronounced in NACT group (p&lt;0.005). Flowcytometry showed FLOT receivers had lower Rh123 accumulation, indicating MDR1overexpression (11.5± 8.9) compared to baseline (49.5 ±38.3). The Pearson χ 2 test revealed positive correlation between ERK1/2 and MDR1 (p=0.000). Conclusions: ERK1/2 and MDR1 found to over-express in stage III, predicts the degree of resistance and MDR phenotype in the GC patients.
A risk-scoring prognostic model of gastric cancer based on angiogenesis.
Authors: Chen Wu, Shuai Li, Xinfang Hou, Su-xia Luo
Journal: Journal of Clinical Oncology (2023)

e16058 Background: Gastric cancer (GC) is a worldwide malignancy that represents a serious threat to human health. However, there is a lack of research on prognostic signatures of angiogenesis and prognosis, immune cell infiltration, and individualized treatment guidance in GC. Methods: Based on NCBI and MsigDB, Angiogenesis-related genes (ARGs) were obtained, and GO and KEGG enrichment analysis were performed. The risk scoring model was constructed by screening ARGs prognosis-related genes through a single-factor COX regression model, combined with Lasso regression to remove redundant factors. The prognostic value was assessed by combining TCGA and GEO databases. Immune infiltration difference analysis was performed. Furthermore, the variability of mutations was analyzed, and CNV differential display was performed. The predictive efficacy for immunotherapy was assessed by analogy to the melanoma immunotherapy suppression data from the GEO. The predictive efficacy of the TIDE assessment risk score for immunotherapy was additionally assessed. Finally, independent prognostic factors of risk scores were analyzed and a nomogram was construction. Results: We finally obtained 575 ARGs, and GO annotation showed that they were associated with angiogenesis, cell migration movement and ligand receptor activity. KEGG showed that it was related to Ras, MAPK and PI3K pathways. A risk score model containing 9 genes was constructed. It was found that the evaluation had a good prognostic value. Analysis of immunoinfiltration differences showed that there were differences. In addition, there was some variability in mutations between the high-risk and low-risk subgroups. It was found to have a better predictive effect of immunotherapy. TIDE assessment risk score was also a good predictor of immunotherapy efficacy. Finally, a nomogram was constructed based on clinical characteristics and risk scores. Conclusions: In this study, a prognostic risk score model for gastric cancer was established, and it was found to have a good predictive effect on immunotherapy effect.
Predicting role of circulating tumor DNA and blood-based tumor mutational burden in esophageal squamous cell carcinoma receiving chemoradiotherapy combined with toripalimab: Exploratory analyses from a phase II trial (EC-CRT-001).
Authors: BaoQing Chen, Shi-Liang Liu, Qiaoqiao Li, Mengzhong Liu, Hong Yang, Mian Xi
Journal: Journal of Clinical Oncology (2023)

4056 Background: EC-CRT-001 is a phase II trial investigating the efficacy of toripalimab (an anti-PD1 antibody) combined with definitive chemoradiotherapy (CRT) in locally advanced esophageal squamous cell carcinoma (ESCC) and the results demonstrated encouraging antitumor activity and acceptable toxicity. This exploratory analysis was performed to evaluate the role of circulating tumor DNA (ctDNA) and blood-based tumor mutational burden (bTMB) for efficacy prediction. Methods: Forty-two patients from the phase II trial (NCT04005170) who received toripalimab (240 mg every 3 weeks for up to 1 year, or disease progression, or unacceptable toxicity) combined with definitive CRT (irradiation with 50.4 Gy in 28 fractions concurrent with 5 cycles of weekly paclitaxel in 50 mg/m 2 and cisplatin in 25 mg/m 2 ) were enrolled. Plasma samples were collected before, during, and after CRT. Targeted next-generation sequencing was performed on a total of 118 plasma samples and 35 matched tumor samples using a panel covering 474 cancer-associated genes. Results: Twenty-six (62%) of 42 patients achieved clinical complete response (cCR) at three months after CRT. ctDNA was detected in 29 (72.5%) of 40 patients at baseline. The positive rate of ctDNA decreased to 43.9% (20/41) during CRT and continued to descend to 27.0% (10/37) at the completion of CRT. A higher cCR rate was observed in patients with negative during-CRT ctDNA compared to those with detectable ctDNA (82.6% vs. 38.9%, P = 0.008). Patients with post-CRT detectable ctDNA also had poorer cCR rate (30.0% vs. 77.8%, P = 0.017). Within a median follow-up of 24.0 months (IQR 13.7-27.9), the median progression-free survival (PFS) was 12.2 months (95%CI: 8.4-16.0) and median overall survival (OS) was not reached for the whole cohort. Patients with during-CRT detectable ctDNA had shorter PFS compared to ctDNA-negative patients (HR = 2.57, 95%CI: 1.18-5.60, P = 0.014). Similarly, patients with post-CRT detectable ctDNA also had a significantly increased risk of disease progression (HR = 2.88, 95%CI: 1.21-6.83, P = 0.012) and death (HR = 3.67, 95%CI: 1.41-9.55, P = 0.004). Moreover, patients with higher bTMB ( &gt; 1) detected during CRT were associated with a favorable OS (HR = 0.33, 95%CI: 0.13-0.88, P = 0.027). Improved PFS was also observed in those patients with higher post-CRT bTMB ( &gt; 3) (HR = 0.28, 95%CI: 0.08-0.96, P = 0.042). Conclusions: Negative ctDNA status and higher bTMB during or after CRT were associated with better tumor response and favorable survival in ESCC patients who underwent definitive CRT combined with toripalimab. Dynamic ctDNA has great potential in predicting efficacy and risk of disease progression in ESCC. Clinical trial information: NCT04005170 .